Cancer is a disease of gene control

The genome codes for "programs" of gene expression that give each cell type its unique identity. Precise control of gene expression ensures that cells develop, grow, and specialize correctly. Cancer corrupts this process to give rise to cells that uncontrollably multiply, grow and invade normal tissues.

The Lin lab uses molecular, computational and chemical biology approaches to study gene control in cancer.

We identify mechanisms that specify, activate, and repress genes that are altered in cancer. We strive to use this knowledge to develop therapeutic strategies targeting the gene control apparatus in cancer and other diseases.

THE MYC PROBLEM

The transcription factor MYC is a master regulator of growth and proliferation. In normal cells, growth factors turn on MYC which binds to DNA and drives gene expression programs required for cells to grow and divide. Many cancers deregulate MYC — elevating its levels and uncoupling normal signals that turn MYC on and off. Our lab studies how deregulated MYC acts as an oncogene and how it reshapes the cell's gene expression program to promote tumor growth. We have learned that MYC acts as a transcriptional amplifier, turning up transcription at all active genes in a cell. We have also found that deregulated MYC can invade tissue specific enhancers that are different in each tumor and often drive tumor specific processes. We are using these insights to develop strategies to target transcriptional co-factors and tumor specific pathways that deregulated MYC uses to drive tumorigenesis.

TARGETING GENE CONTROL

Inhibition of chromatin and transcriptional regulators can often have highly selective effects on tumors despite the fact that these regulators are expressed in many cell types and often regulate many thousands of genes. Our lab seeks to uncover the underlying mechanisms behind this selectivity. To do so we use approaches to map where these regulators bind to the genome and we develop perturbation systems to profile and model the consequences of their inhibition. We have found in many cancers that chromatin and transcriptional regulators congregate at a small number of "super-enhancer" loci that regulate critical oncogenes and are highly sensitive to transcriptional perturbation. We seek to exploit these vulnerabilities through the use of highly selective small molecule chemical probes and through chemical biology strategies to develop and characterize novel agents.

Modeling tumor ORIGINS

Understanding the cellular origins of tumors can provide new ways to model disease phenotypes and identify lineage specific targets. Transcription factors that specify tissue specific gene expression programs are considered master regulators of cellular identity. These master regulatory transcription factors often form a regulatory circuitry where in any given tumor or tissue a small number of master regulatory transcription factors form super-enhancers and are regulated by super-enhancers. By analyzing regulatory circuitries formed by super-enhancers, enhancers and transcription factors, our lab can infer putative master regulatory transcription factors and the DNA elements that regulate their expression. This has allowed us to develop systems to trace tumor origins and to also devise new strategies to target the cells of origin that give rise to cancer.